Role of FET proteins in neurodegenerative disorders

Francesca Svetoni, Paola Frisone, Maria Paola Paronetto, Francesca Svetoni, Paola Frisone, Maria Paola Paronetto

Abstract

Neurodegenerative disorders such as Alzheimer disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) affect different neuronal cells, and have a variable age of onset, clinical symptoms, and pathological features. Despite the great progress in understanding the etiology of these disorders, the underlying mechanisms remain largely unclear. Among the processes affected in neurodegenerative diseases, alteration in RNA metabolism is emerging as a crucial player. RNA-binding proteins (RBPs) are involved at all stages of RNA metabolism and display a broad range of functions, including modulation of mRNA transcription, splicing, editing, export, stability, translation and localization and miRNA biogenesis, thus enormously impacting regulation of gene expression. On the other hand, aberrant regulation of RBP expression or activity can contribute to disease onset and progression. Recent reports identified mutations causative of neurological disorders in the genes encoding a family of RBPs named FET (FUS/TLS, EWS and TAF15). This review summarizes recent works documenting the involvement of FET proteins in the pathology of ALS, FTLD, essential tremor (ET) and other neurodegenerative diseases. Moreover, clinical implications of recent advances in FET research are critically discussed.

Keywords: ALS; EWS; FUS; TAF15; neurodegenerative disorders.

Figures

Figure 1.
Figure 1.
Schematic representation of the 3 members of the FET family (FUS, EWS and TAF15). FET proteins share the same domain structure. SYGQ = serine, tyrosine, glycine and glutamine; RGG = represents a region enriched in arginine-glycine-glycine motifs; RRM = RNA-binding domain; ZF = Cys2/Cys2-type zinc finger motif; PY = proline-tyrosine nuclear localization signal (NLS). In the figure, a schematic overview of FUS, EWS and TAF15 mutations identified in ALS patients is represented. del = deletion; ins = insertion; fs = frameshift; X = stop.
Figure 2.
Figure 2.
Impairment of nucleo-cytoplasmic shuttling of FET proteins contributes to neurodegenerative disease and muscular atrophy. In normal conditions, FET proteins display several physiological functions, including transcription, pre-mRNA splicing, mRNA biogenesis, stress granules formation and mRNA stability, by binding target RNAs both in the nucleus and in the cytoplasm and are engaged in nucleo-cytoplasmic shuttling (a). Mutations within the NLS or NES of FET proteins and factors arising during aging, like reduced expression of nuclear transport factors or oxidative damage, as well as post-translational modifications, such as phosphorylation, arginine methylation and proteolytic cleavage events that remove the NLS, can cause cytoplasmic accumulation of FET proteins within stress granules (b). Such stressors may also include environmental toxins or mutations in neuro-protective/stress protective genes, such as GRN or VCP. Since the formation of stress granules is a reversible process, this step can potentially be reversed upon release of stress or by upregulation of protective factors, like chaperones or neuronal growth factors, such as Progranulin. However, persistent cellular stress or genetic risk factors leads to the conversion of FET-containing stress granules into large pathological inclusions. This in turn can cause degeneration of motoneurons and muscular atrophy (c).

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